Giotrif 40mg Boehringer medicine for lung cancer treatment (4 blisters x 7 tablets)
Dosage form Box of 4 blisters x 7 tablets
Specifications Afatinib
Ingredient
| Composition information | Content |
| Afatinib | 40mg |
Uses
Indications
Giotrif monoma is indicated for treatment of non -small cell lung cancer in the spot or metastasis with mutations of receptors of epidermal growth factors (EGFR) for adult patients who have not been treated earlier with EGFR Tyrosine Kinase inhibitors.
Pharmacokinus
Pharmacological treatment group: Other anti -cancer drugs - inhibit protein kinase.
ATC code: l01xe13.
Mechanism of action:
Afatinib is an ErBB inhibitor that has a strong, selective and non -recovery effect. Afatinib binds covalent and inhibited non-recovery signals from Homo- and Heterodimer formed by members of the ERBB group: EGFR (ERBB1), Her2 (ERBB2), ERBB3 and ERB4.
Pharmacological effects:
Erbb signal may be triggered by mutations and/or amplifiers of EGFR, amplifier or mutations Her2 and/or increase the expression of Ligand ERBB contributes to creating abnormal characteristics in patients subgroups with many different types of cancer.
In the preclinical pathological models that have lost control of the ERBB route, Afatinib uses a single substance that effectively inhibits the signal transmission of the ERBB receptor that inhibits tumor growth or degrees of tumor. The NSCLC model with L858R or Del 19 EGFR mutations is particularly sensitive when treated with Afatinib. Afatinib maintains a significant tumor resistance in NSCLC in vitro cell lines and in vivo tumor models (transplanted with genetically transferred models) determined by the mutant EGFR -like similarity such as T790M which is determined to be resistant to EGFR inhibitors with Ellotinib and Gefitinib.
pharmacokinetics
absorption and distribution:
After taking Giotrif, the maximum concentration (cmax) of Afatinib is observed about 2 to 5 hours after taking the drug. The average CMAX and AUC0 -∞ value increases slightly than the ratio in the giotrif dose range from 20 mg to 50 mg. Afatinib's systemic concentration decreased by 50% (CMAX) and 39% (AUC0-fit), when taken with food rich in fat compared to when drinking hungry. Based on the dynamic dynamic data obtained from clinical trials with different types of tumors, see AUCT, S decreased on average 26% when eating within 3 hours before or 1 hour after giotrif. Therefore, do not eat for at least 3 hours ago and within 1 hour after taking Giotrif (see "dosage and usage" and "interaction"). After using Giotrif, relatively average bioavailability is 92% (the average ratio of the adjustment of AUC0-∞) when compared to the oral solution.
In vitro afatinib is connected to protein in human plasma about 95%.
Metabolism and elimination:
The metabolic reactions by catalytic enzymes play a negligible role for Afatinib In Vivo. Products that connect covalent with protein are the main metabolites of Afatinib.
After taking 15 mg of Afatinib in the form of solution, 85.4% of the dose is found in feces and 4.3% in urine. The initial Afatinib compound accounts for 88% of the detected dose. The last elimination selling time is 37 hours. The plasma concentration in the stable state of Afatinib is achieved within 8 days after taking multiple doses of Afatinib causing AUC accumulation 2.77 times and CMAX is 2.11 times.
Population pharmacokinetics analysis in special population group:
Popular pharmacokinetics analysis is conducted on 927 cancer patients (764 with NSCLC) using single -treatment Giotrif. It is not necessary to adjust the starting dose for any number of numbers studied below.
Age:
Not observing significant impact of age (range 28-87 years) to pharmacokinetics of Afatinib.
Body:
Plasma concentrations (AUCT, SS) increased by 26 % in patients 42 kg (2.5 %) and decreased by 2 % in patients 95 kg (97.5 %) compared to patients 62 kg (the average body of patients in the general test population).
Sex:
Plasma concentrations over time of female patients are 15 % higher (AUCT, SS, seriously corrected) compared to male patients.
Race:
There is no significant difference of statistical significance of pharmacokinetics between Asian patients and white skin. There is also no clear difference in pharmacokinetic pharmacokinetics for native aboriginal/Alaska -based people or black skin patients based on limited data available in these populations (equivalent 6 and 9 patients among 927 patients are put into analysis).
kidney failure:
less than 5% of the Afatinib's single dose is eliminated through the kidneys. The concentration of Afatinib in patients with renal impairment is compared to a healthy volunteer after taking a single dose of 40 mg of Giotrif. Medium renal failure objects (n = 8, eGFR 30-59 ml/min/1.73m2, according to the diet adjustment formula in kidney disease [MDRD]) has a concentration of 101% (cmax) and 122% (AUC0-TZ) compared to healthy control groups. Subjects of severe renal failure (n = 8, eGFR 15-29 ml/min/1.73m2, according to the formula MDRD) have a concentration of 122% (cmax) and 150% (AUC0-TZ) compared to a healthy control group. Based on this clinical trial and the population data data obtained from clinical trials on many different types of tumors, it is not necessary to adjust the starting dose in patients with mild renal impairment (EGFR 60-89 ml/min/1.73m2), average (EGFR 30-59 mL/min/1.73m2) or heavy (EGFR 15-29 mL/min/1.73m2) use). There is no study using Giotrif for patients with EGFR
Giotrif's time concentration increases relatively when the creatinine (CrCl) clearance is low, for example, for patients with 60 or 30 ml/minute CrCl, the concentration over time (AUCT, SS) of Afatinib increases as 13% and 42%, and down 6% and 20% corresponding to CrCl 90 or 120 ml/minute patients compared to CrCC 79 mL/minute (CRCL accumulation).
Hepatic failure:
Afatinib is excreted mainly through bile/fertilizer. People with mild liver failure (Child Pugh A) or medium (Child Pugh B) achieve the same concentration as healthy volunteers after taking the only dose of Giotrif 50 mg. This is consistent with the dynamic dynamic data obtained from clinical trials on many different types of tumors (see "" The pharmacokinetic analysis of the population in special population "below). There is no need to adjust the starting dose in patients with mild or medium liver failure (see "dosage and usage"). The pharmacokinetics of Afatinib has not been studied in severe liver failure (Child Pugh C) (see "Caution and Warning Special").
Patients with mild to moderate liver failure are determined by abnormal liver function tests that are not correlated with any significant changes to Afatinib levels.
Other characteristics of patients /internal factors:
Other characteristics of patients/intrinsic factors are significantly affected by Afatinib concentration: Ecog points, Dehyhydrogenase levels, phosphorus alkalin concentrations and total proteins. The specific influence of these variables is thought to be clinically significant. History of smoking, drinking alcohol, or liver metastasis does not significantly affect the pharmacokinetics of Afatinib.
Before taking Giotrif 40mg Boehringer medicine for lung cancer treatment (4 blisters x 7 tablets)
How to use
should not take Giotrif with food. Do not eat at least 3 hours ago or at least 1 hour after taking Giotrif (see "interaction" and "pharmacokinetics"). Should swallow the tablet with water.
Other usage:
If you cannot take the whole pill, you can mix Giotrif in about 100 ml of carbonate -free drinks. Do not use other solutions. Put the pills into the water and not be grinded, occasionally stirring for 15 minutes until the pill is disintegrated into very small particles
Dosage
Non -small non -cell lung cancer (NSCLC):
Giotrif dose recommends that 40 mg oral once a day for step one or for patients who have not been treated earlier with EGFR Tyrosine Kinase inhibitors (patients have never used EGFR TKI).
Should be treated with Giotrif continuously until the disease progresses or the patient is no longer tolerated (see Table 1 below).
Dose increase
It is possible to consider increasing the maximum dose of 50 mg daily in patients who have never used EGFR TKI and tolerated 40 mg daily (i.e. without diarrhea, rash, stomatitis and other drug -related events with a level of> 1 according to CTCAE) for the first 3 weeks. The dose should not be increased in patients who have reduced the previous dose.
In any case, the maximum daily dose is 50 mg.
Adjust the dose due to adverse reactions
The adverse reaction that causes symptoms related to drugs (such as severe/prolonged diarrhea or adultery reactions on the skin) can be well treated by temporary suspension of treatment and reduction of giotrif dose as stated in Table 1 (see "Side effects"; for more details on how to handle specific adverse events due to the drug "Warning and special cautious").
Side Effects
Summary of safety characteristics
Unwanted effects (ADR) generally related to EGFR inhibitors in Afanitib activity. All unwanted effects are synthesized in Table 2. The most unwanted effect is diarrhea and adultery events on the skin (see the warning and special caution) and stomatitis, inflammation around the nail (see also Table 3).
In general, reducing the dose leads to reducing the frequency of side effects often (see the dose and usage section).
In patients treated with Giotrif 40 mg once a day, reducing the dose due to unwanted effects occurs in 57% of patients in Lux-Lung 3 clinical trial. Stop drugs due to unwanted effects of diarrhea and acne rashes are 1.3% and 0% in Lux-Lung 3 test.
Reactions like interstitial lung disease are reported in 0.7% of patients treated with Afatinib. There has been a report on the case of water glossy, blistering, scales, including rare cases suggesting Stevens-Johnson syndrome and poisoned epidermal necrosis although these cases may be due to other causes (see the warning and special caution)
List of unwanted effects
Table 2 Summary of the frequency of unwanted effects from NSCLC tests and from experience used after Giotrif Circulation at a dose of 40 mg or 50 mg of monochromatic therapy. The following terms are used to classify unwanted effects by frequency: Very common (≥1/10); popular (≥1/100 to 1/10000 to
Warnings
Before using the drug you need to read the instructions carefully and refer to the information below.
contraindicated
contraindicated use of giotrif for patients with hypersensitivity to afatinib or any excipient.
Be cautious when using
evaluate the situation of EGFR mutations
When assessing the condition of EGFR mutations in a patient, it is important to choose an accurate method and have been carefully evaluated to avoid fake or false negative results.
diarrhea
diarrhea, including severe diarrhea, has been reported during treatment with Giotrif (see "side effects"). Diarrhea can lead to dehydration or no renal failure, in rare cases that can lead to death. Diarrhea usually appears in the first 2 weeks of treatment. Level 3 diarrhea usually appears in the first 6 weeks of treatment. It is important to proactively treat diarrhea including enough water to combine with anti -diarrhea drugs for the first 6 weeks of treatment and start as soon as there are first signs of diarrhea. Anti -diarrhea should be used (such as Loperamid) and if necessary, the highest recommended dose should be approved. An anti -diarrhea should be available so that patients can be treated when they have the first sign of diarrhea and should be treated continuously until it is gone to a loose stool for 12 hours. Patients with severe diarrhea may need to suspend the drug and reduce the dose or permanently stop treatment with Giotrif (see "dosage and usage"). Patients dehydration may need intravenous and electrolyte infusion.
Skin adultery
There has been a report on acne/acne in patients treated with giotrif (see "side effects"). In general, the board manifests itself in the form of a light or medium erythema and an acne -like rash that may appear or get worse in areas exposure to the sun. Patients who are exposed to sunlight should be advised to use covered clothes, and/or sunscreen. Early intervention of skin reactions (such as skin softening cream, antibiotics) can facilitate continuous treatment with giotrif.
Patients with prolonged or serious skin reactions may also need to be temporarily stopped, reduce the dose (see "dosage and use"), additional treatment, and examining a dermatologist to treat skin effects. There has been a report on the case of water glossy, blistering, scales, including rare cases suggesting Stevens-Johnson syndrome and poisoned epidermal necrosis.
Should suspend or permanently stop treatment with Giotrif if the patient shows signs of glossy skin, blistering or severe peeling.
Women's patients, mild weight and renal failure
Observed a high concentration of Afatinib in female patients, mild weight and patients with renal failure (see "pharmacokinetics"). This may increase the risk of adverse events through EGFR intermediaries such as diarrhea, rash/acne and stomatitis. Should closely monitor patients with these risk factors.
Interstitial lung disease (ILD)
There have been ILD reports or ILD -like events (such as pulmonary infection, pneumonia, acute respiratory insufficiency syndrome, allergic alveoli), including deaths in patients using Giotrif to treat NSCLC. ILD -like events related to drugs are reported at 0.7% of more than 3800 patients treated. ILD -like events at ≥ 3 according to CTCAE, regardless of cause and effect, are reported in 1% of patients (see "side effects"). No research in patients with a history of ILD. Careful evaluation of all patients with symptoms in the lungs (shortness of breath, cough, fever) manifest acute and/or bad progression for unknown reasons to eliminate iLD. Giotrif treatment should be suspended while waiting to evaluate symptoms. Giotrif should be stopped permanently if diagnosed with ILD and appropriate treatment when needed (see "dosage and usage").
Severe liver failure
Hepatic failure, including death, has been reported during Giotrif treatment at less than 1% of patients. In these patients, jamming factors include liver disease that has existed before and/or diseases that come with the progression of malignant tumors. Liver function should be checked periodically for patients who have had liver disease in advance. Giotrif may be temporarily suspended in patients with deteriorating liver function (see "dosage and usage"). Giotrif should be stopped permanently if the patient appears serious liver failure during medication.
Cerematitis
Need to see an eye specialist immediately if there are symptoms of acute or bad inflammation, watery, light sensitivity, blurred vision, eye pain and/or red eye. If diagnosed with corneal ulcers, it is recommended to suspend or permanently stop treatment with giotrif. If diagnosis of keratitis should be careful between the benefits and risks of continuing treatment. Be cautious when using Giotrif for patients with a history of keratitis, corneal ulcers or severe dry eyes. Using contact lenses is also a risk factor for keratitis and ulcer (see "side effects").
Left ventricular function
left ventricular dysfunction is associated with HER2 inhibition. Based on the existing clinical data, there is no suggestion showing that Giotrif has a disadvantageous effect on heart contractions. However, there is no study of Giotrif in patients with abnormal LVEF blood vessels (LVEF) or a history of severe heart disease. In patients with heart risk factors and patients who may affect LVEF, cardiovascular monitoring should be considered, including LVEF evaluation at the beginning and during Giotrif treatment. If the patient appears the signs/symptoms related to the heart during treatment, cardiovascular monitoring includes LVEF reviews. In patients with lower hematoma than the lower limit of the normal level as prescribed, the cardiovascular specialist should be examined as well as the temporary suspension or permanent suspension of giotrif.
Interaction with P-Glycoprotein inhibitors (P-GP)
Using strong P-GP inhibitors before using Giotrif may cause an increase in concentration over time of afatinib and thus use caution. If you need to use P-GP inhibitors, you should use it at the same time or after giotrif. Simultaneous treatment with strong P-GP induction drugs can reduce the concentration over time of Afatinib (see "dosage and usage", "interaction" and "pharmacokinetics").
Combined with Vinorelbin in metastatic breast cancer with her2 positive
In a mid -term analysis of the entire survival during the first time of a phase III study in metastatic breast cancer with a positive Her2 showed an increase in the mortality rate in patients using Giotrif in combination with Vinorelbin compared to using Trastuzumab and Vinorelbin. Combining Giotrif with Vinorelbin also increases the adverse effect rate (such as diarrhea, rash) and fatal events associated with progressive bacterial infections and cancer. Giotrif should not be used in combination with vinorelbin for patients with metastatic breast cancer with a positive Her2.
lactose
Giotrif contains lactose. Patients with rare genetic diseases are galactose intolerance, such as Lapp Lactase deficiency or Glucose-Galactose, which should not be taken.
The effect of the drug on driving and operating machinery
There is no study on the ability to drive and operate machinery.
Using drugs for women during pregnancy and lactation
pregnancy:
Clinical studies with Afatinib show that there is no sign of teratogenicity when using the mother's death. The adverse changes only appear at clearly toxic doses (see "toxicity").
There is no study in pregnant women using Giotrif. Therefore, the potential risk in people is unknown. Women who have the ability to give birth should be advised to avoid getting pregnant during giotrif treatment. Appropriate contraceptive measures should be used during the medication period and at least 2 weeks after the last dose of the drug. If Giotrif is used during pregnancy or if the patient is pregnant during giotrif, it is advisable to notify the patient the potential dangers for the fetus.
breastfeeding:
Based on clinical data (see "toxicity"), capable of Afatinib is excluded into breast milk.
cannot rule out the risk of breastfeeding. Mothers should not breastfeed when using giotrif.
Reproduction:
There is no Giotrif research on human fertility. Clinical non -clinical toxic data has been proven to affect the reproductive organs when high doses (see "toxicity"). Therefore, it is not possible to eliminate adverse effects on fertility in humans when treated with giotrif.
Drug interaction
Interactions with drug transport system
Effects of P-GP inhibitors and anti-drug protein inhibitors in breast cancer (BCRP) on Afatinib:
In vitro studies have shown that Afatinib is the substrate of P-GP and BCRP. When using a strong P-GP and BCRP inhibitor is Ritonavir (200 mg twice a day for three days) an hour before using a single dose of 20 mg of Giotrif, Afatinib concentration increases 48% (the area under the curve (AUC0 -∞)) and 39% (cmax peak concentration (CMAX)). On the other hand, when using Ritonavir simultaneously or 6 hours after using 40 mg of Giotrif, the relative bioavailability of Afatinib is 119% (AUC0 -∞), 104% (cmax) and 111% (AUC0-fit), 105% (cmax). Therefore, it is recommended to use strong p-GP inhibitors (including but not only limited to ritonavir, cyclosporine A, ketoconazole, iTraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquavir, and amiodarone) SO LO Compared to giotrif (see the dosage and usage).
Effect of P-GP induction drugs on Afatinib:
Previous treatment with Rifampicin (600 mg once a day for 7 days) is a strong stimulant P-GP that reduces the concentration of Afatinib 34% (AUC0 -∞) and 22% (CMAX) after the only dose of Giotrif 40 mg. Strong P-GP induction drugs (including but not only limited to rifampicin, carbamazepine, phenytoin, phenobarbital or St. John's herbal (Hypericum Perforatum) can reduce Afatinib levels (see the warning and special cautious).
The influence of afatinib on the substrate of P-GP:
Based on in vitro data, Afatinib is an average P-GP inhibitor, however, based on clinical data, treatment with Giotrif is considered not to change the concentration of plasma of the substrates of P-GP.
Interaction with BCRP:
In vitro studies show that Afatinib is a substrate and a BCRP transportation inhibitor. Afatinib may increase the bioavailability of oral BCRP substrates (including but not only limited to rosuvastatin and sulfasalazine).
The effect of food on Afatinib
Giotrif drinking with a fat-rich meal significantly reduces the concentration over time of Afatinib, specifically CMAX decreased by 50% and AUC0-∞ decreased by about 39%. Therefore, Giotrif should therefore be with food (see "dosage and usage" and "pharmacokinetics").
Storage
Store no more than 30 ° C.
Store in the original packaging to avoid moisture and light.
To be out of reach of children.
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